1-dehydro-11-keto-9alpha-fluoro-17alpha-methyl testosterones



United States Patent 3,166,644 l-DEHYDRG-11-KETO-9a-FLUOR$=17- METHYL TESTOSTERQNES Milton E. Herr, Kalamazoo Township, Kalamazoo County, Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Mich gan No Drawing. Filed Aug. 8, 1955, Ser. No. 527,118

a 2 Claims. (Cl. 260-49145) This invention relates to novel l7-alkyl-l7-hydroxy steroids and esters thereof.

It is an object of this invention to provide novel 90:- halo-1lfi-hydroxy-l7-alkyltestosterones, 9a-halo-l l-ketol7-alkyltestosterones, l7-esters thereof, md intermediates in the production thereof. Another object is the provision of processes for the production thereof. Other objects will be apparent to those skilled in the art to which invention pertains.

According to the present invention, the novel 9a-halo- 1l[3-hydroxy-l7-alkyltestosterones, 9a-halo-1l-keto 17 alkyltestosterone and l7-esters thereof may be prepared from 9(11)-dehydro-17-alkyltestosterone via the known 3 -pyrrolidyl enamine of 4,9(11)-androstadiene-3,17- dione (II) [Heyl and Herr, I. Am. Chem. Soc., 77, 489 (1955)], 1lfl-hydroxy-17-methyltestosterone or esters thereof (1) or 11a-hydr0xy-l7-methyltestosterone or esters thereof (US. Patent 2,660,586) (I) as shown by the following formulae:

on, CH3

o-n'. 0 I CHa CH3 CH5 l w 7 I v H CH3 CH3 0-11" L R nmfi i o i R no f X 0H:

- V VI X! Y om Qua-fiUOI'O and 9a-chloro compounds;

wherein R is a lower-alkyl group containing less than three carbon atoms, i.e., methyl or ethyl; R is hydrogen or the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive; X is a halogen having an atomic weight from 79 to 127, inclusive, i.e., bromine or iodine, X is a halogen having an atomic weight from 19 to 36, inclusive, i.e., fluorine 'or chlorine, and X" is a halogen having an atomic weight from 19 to 127, inclusive, i.e., fluorine, chlorine, bromine or iodine.

Following the series of reactions described hereinafter for the conversion of 1la-hydroxyl7-methyltestosterone (l) to 9ct-tluoro-ll,G-hydroxy-l7-methyltestosterone and esters thereof (VII), but substituting 10-normethyl-11ahydroxy-l7-methyltestosterone (US. Patent 2,660,586) as the starting steroid, there are thus-produced 9a-fl1lOI0-10- norrnethyl-llfl-hydroxy 17 methyltestosterone and 17- esters thereof. These compounds are also potent oral anabolic agents possessing androgenic activity.

Reacting 9(11)-dehydro-l7-methyltestosterone with a molar excess of diethyl oxalate and a molar equivalent of sodium methoxide in tertiary butyl alcohol is productive of the sodium enolate of the Z-ethoxyoxalyl derivative .thereof. After neutralization of the solution with acetic acid and then brominating with a molar equivalent of bromine at about minus ten degrees centigrade, 2- bromo 2 l ethoxyoxalyl-9 l 1 -dehydro-l7-methyltestosterone is produced. After removing the 2-ethoxyoxalyl group with sodium methoxide in methanol, the 2-,brorno- 9(11) -dehydro-l7-methyltestosterone is dehydro-halogenated with refluxing collidine to 3-keto-17u-methyl- 2,4,9(11)-androstatrien-l7fi-ol. Employing this compound as the starting steroid in the reactions for the conversion of 9(l1)-dehydro-17-methyltestosterone to cfiuoro-llfi hydroxy-l7-methylte tosterone and 17-esters thereof, there are thus-produced 3-k6t0-9a-fl1101'0-17umethyl-ZA-andmstadiene-l1,8,l7fi-diol and 17-esters thereof, e.g., a hydrocarbon carboxylic acid ester containing from one to twelve carbon atoms, inclusive, for example, of an acid named in the paragraph following Example 4. These compounds also possess androgenic activity and marked oral anabolic activity.

The novel 9u-halo-l1fi-hydroxy-17-alkyltestosterone and l7-esters thereof (VII) and 9a-halo-ll-keto-7-alkyltestosterone and l7-esters thereof (VIII) possess marked androgenic activity and oral anabolic'activity. For example, 9a-fluoro-1lfl-hydroxy-17-methyltestosterone possesses an oral anabolic activity about. eighteen to nine teen times and an oral androgenic activity about ten times that of l7-methyltestosterone. Furthermore, it is considerably less toxic and, surprisingly, it does not demonstrate the undesirable salt retention side-eifect which one might expect of a 9a-fiuoro compound. 9 -fluoro- 1l-keto-l7-methyltestosterone possess an oral androgenic activity which is more than twice that of 17-methyltestosterone and its oral anabolic activity is more than five times that of 17-methyltestosterone. Similarly, the cor-. responding 9ix-chloro analogues possess high oral anabolic and androgenicacu'vities as do the l7-esters of both the 9a-b10m0- and 9a iodo-1 l-ketm17-methyltestosterone and their 17-esters also possess anabolic and androgenic activity..

The novel androgens andanabolic agents of tins invention, especially VII and VIII, are useful as male gonadal} replacement therapy in prepuberal and postpuberal castrates, in pituitary dwarfism, Simmonds disease, dysmenorrhea and for suppression of lactation. Their anabolic nitrogen balance in pituitary deficiencies. By adjustment of the dose, a favorable anabolic response can be achieved without noticeable androgenic response, if this is desired.

The novel androgen and anabolic agents of the present invention are normally administered orally, e.g., as tablets, capsules or in the form of flavored fluid preparations, in which may additionally be incorporated, if desired, an estrogen, e.g., estrone, estradiol, ,B-cyclopentylpropionate, for combined androgen-estrogen therapy.

The following examples are illustrative of the products and processes of the present invention, butare not to be construed as limiting.

EXAMPLE 1 9 (11 -Dehydro-J 7-M ethyl testosterone (IV) To a stirred solution of grams of ll,8hydroxy-4- andr ostene-3,17-dione in one liter of dry pyridine was added, at room temperature and in a nitrogen atmosphere, sixty grams of N-bromoacetamide all at once. The resulting mixture was stirred for fifteen minutes and then cooled to ten degrees Centigrade. into the cooled solution was bubbled sulfur diox de gas until the mixture gave a negative test with acidified starch-iodide paper. The mixture was diluted with four liters of water and cooled to about zero degrees centigrade for three hours. There was thus precipitated 4,9(ll)-androstadiene-3,l7-dione [Heyl and Herr, J. Am. Chem. Soc., 77, 488 (1955)] which after filtering, washing with water and drying, weighed eighty grams and melted at 197 to 203 degrees centigrade.

To a hot solution of 56.8 grams of 4,9 (.ll)-'andr.ostadiene-3,l7-dione in 800 milliliters of methanol was added 25 milliliters of pyrrolidine, whereupon product began to precipitate almost immediately. The solution was permitted to cool to room temperature and then was refrigerated at zero degrees centigrade for three hours. The crystalline precipitate was filtered, washed with methanol and then dried to give 59 grams of the B-enarnine of 4,9(11) androstadiene-Il,l7-dione (II) (3-pyrrolidyl- 3,5,9(ll)-androstatrien-l7-one) (Heyl and Herr, lo c. cit.) melting with decomposition above degrees centigrade.

T o a stirred solution of 700 milliliters of a four molar solution of methyl magnesium bromide in diethyl. ether was added, dropwise and in anitrogen atmosphere, 2. solution of 59 grams of the 3-cnamine of 4,9(ll)-androstadiene-3,l7-dione (II) in one liter of strictly anhydrous tetrahydrofuran over a period of fifteen minutes. When addition was complete the mixture was warmed and the solvent distilled therefrom until the distillation temperature reached sixty degrees Centigrade. While protecting under. a nitrogen atmosphere, there was then added 7.60 V

milliliters of glacial acetic acid followed by one liter of methanol and the mixture. was then heated until all the tional fifteen minutes.

4 milliliters of methylene chloride and 250 milliliters of benzene and chromatographed over 700 grams of activated alumina. The column was developed with 500 milliliters of benzene, two liters of Skellysolve B hexane hydrocarbon plus four percent acetone, two liters of Skellysolve B plus seven percent acetone, two liters of Skellysolve B plus eleven percent acetone, four liters of Skellysolve B plus fourteen percent acetone and finally, two liters of Skellysolve B plus seventeen percent acetone. The eluate fractions containing from eleven to seventeen percent acetone were combined and the solvent distilled therefrom to give crude product which, when crystallized from dilute acetone, gave 26.8 grams of 9(l1)-dehydrol7-methyltestosterone (IV) melting at 167 to degrees Centigrade.

Following the procedure of Example 1 exactly, but substituting ethyl magnesium bromide for the methyl magnesium bromide, there is thus-produced 9(ll)-dehydroxy-17-ethyltestosterone.

EXAMPLE 2 V 9 (I -Dehydr0-1 7-Methyltestoster0ne (I V) One-half gram of ll-keto-l7a-methyltestosterone (U.S. Patent 2,678,933) was dissolved in three milliliters of absolute methanol and mixed with one-half milliliter of pyrrolidine at a temperature of about fifty degrees centigrade. The mixture was allowed to cool to room temperature, and, after about one-half hour, the S-enamine of 1l-keto-l7-methyltestosterone [3-(N-pyrrolidyl)-l7amethyl-17,8-hydrox -3,5-androstadien-ll-one] which had precipitated was removed by filtration and dried under vacuum. The yield of high purity 3-enamine product was 0.452 gram melting at to degrees centigrade with decomposition.

A solutionof 1.79 grams of the 3-enamine of ll-ketol7oc-methyltestosterone in a mixture of 25 milliliters of thiophene-free benzene and 25 milliliters of anhydrous ether was added dropwise with mechanical stirring to a mixture of one-half gram of lithium aluminum hydride: and 85 milliliters of dry ether. The addition required about five minutes and stirring was continued for an addi- Then with stirring, ten milliliters of ethyl acetate was cautiously added dropwise, followed by ten milliliters of water. The resulting mixture was concentrated in vacuo to a thick slurry. One hundred milliliters of methanol was then added and the mixture stirred for ten minutes at a temperature of about fifty degrees centigrade. Then eighteen milliliters of five per cent aqueous sodium hydroxide was added and the stirring continued at the same temperature for another ten minutes. After addition of five milliliters of acetic acid, the mixture was concentrated in vacuo. A mixture of fifty milliliters of water and eight milliliters of concentrated hydrochloric acid was added, and the solid product was precipitated- '3 -enamine of 9(11)-dehydrol7-methyltestosterone (111) had dissolved.

To the solution containing the S enamine of 9(l1)-dehydro-17-methyltestosterone (III) was then added 700. milliliters of ten percent aqueous sodium hydroxide and' the mixture was then heated at its refluxing temperature i for thirty minutes to hydrolyze the enamine group, there by regenerating the -A 3-keto. group. The mixture was then cooled to room temperature, acidified with acetic acid and then distilled at reduced pressure until a residual volumeof about 1.5 liters was reached; After, adding a,

mixture of 100 milliliters of concentrated hydrochloric acid and 100. grams of ice, the residue was extracted with 800, 500, 400 and 400 milliliter portions of methylene chloride. The combined extracts were washed successively with water, dilute sodium hydroxide and water and then dried. The solvent was distilled. fromthe dried solution and the residue dissolved in a mixture of 100.

recovered by filtration, washed with water, and dried in air. The yield of 1IB-hydroxy-17u-methy1testosterone (I) was 1.29 grams; melting point 207 degrees-centigrade.

ecrystallization from a mixture of methylene chloride and Skellysolve B hexane hydrocarbons gave 0.977 grams of ll ,B-hydroxy-17a-methyltestosterone; meltingpoint 209 to 211 degrees centigrade and having an of plus 128 degrees in chloroform.

Analysis.--Calculated for C H O C, 75.44; H, 9.49. Found: C, 75.14; H, 9.85. 7

To a stirred solution of one gram of 11/3-hydroxy-l7 methyltestosterone (I) in ten milliliters of dry pyridine was added, portionwise at 25 degrees centigrade and in a nitrogen atmosphere, 0.5 gram of N bromoacetamide.

Stirring was continued for fifteen minutes, the mixture then cooled to ten degrees centigrade and sulfur dioxide gas was bubbled into the cool solution until a negative tated solid was separated, washed with water, dried and then crystallized first from a mixture of methylene chloride and Skellysolve B (hexane hydrocarbons) and then from dilute acetone to give 9(11)-dehydro-17-methyltestosterone melting at 170 to 172 degrees centigrade.

EXAMPLE 3 9 (1 1 -Dehydr-1 7 -M etrzylzestoszeron e (IV) A warm solution of one gram of 11a-hydroxy-l7-methyltestosterone (I, US. Patent 2,660,586) in two milliliters of dry pyridine was mixed with one gram of paratoluenesulfonyl chloride. The mixture was maintained at room temperature for eighteen hours and then poured into 25 milliliters of water. The mixture was stirred until the precipitated oil solidified. The solid was filtered, washed With water and dried to give 1.41 grams of lla-(p-toluenesulfonyloxy)-17o-methyl-17-hydroxy 4 androsten-3- one which melted at 144 to 148 degrees Centigrade with decomposition and, after crystallization from a mixture of methylene chloride and hexane hydrocarbons, melted at 141 to 144 degrees Centigrade with decomposition and had an [ab of plus 41 degrees in chloroform and the analysis below.

Calculated for C H O S: C, 68.61; H, 7.68; S, 6.78. Found: C, 68.86; H, 7.86; S, 6.89.

A mixture of one gram of the thus-produced lla-(ptoluenesulfonyloxy)-17a-methyl 17,8 hydrox -4-androsten-3-one, 0.2 gram of sodium formate, 0.57 milliliter of water and fourteen milliliters of absolute ethanol was heated at its refluxing temperature for nineteen hours. The solution was cooled and then poured onto fifty grams of a mixture of ice and water with stirring. The resulting precipitate was filtered and dried to give 0.59 gram of 9(1l)-dehydro-l7-methyltestosterone which melted at 156 to 160 degrees centigrade and, after crystallization from a mixture of methylene chloride and hexane hydrocarbons, melted at 167 to 170 degrees centigrade and had an [@1 of plus 57 degrees in chloroform and the analysis below.

Calculated for C H O C, 79.96; H, 9.39. Found: C, 79.59; H, 9.08.

EXAMPLE 4 9 (11 -Dehydr0-1 7 -M ethyl testosterone, 1 7 -A cetate (I V) A solution of 9 (11)-dehydro-l7-methyltestosterone in dry pyridine was treated with acetic anhydride, themolar ratio of steroid to acetic anhydride being about one to three, and the resulting mixture was heated under reflux for six hours. The mixture was then cooled, diluted with water while stirring, and the solid precipitate obtained removed by filtration. The solid was washed with two percent aqueous hydrochloric acid solution and with water, and then dried under vacuum. Recrystallization or chromatographic separation provides purified 9(1l)-dehydro-l7-methyltestosterone, 17-acetate. Similarly, 9(1l)- dehydro-l7-methyltestosterone is converted to other 9(11)-dehydro-l7-methyltestosterone, 17-acylates by esterification of the 17-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride orbromide, ester by ester exchange, acid in the presence of esterification catalyst, etc. Examples of 9(11)-dehydro-l7-meth-, yltestosterones, 17-acylates (1V, R CE-l R' Acyl') prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic, di thylacetic, triethylacetic, heptanoic, 'octanoic, u-ethylisovaleric, or other hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, e. g., cyclopropylideneacetic, cyclopentylformic, cyclopentylacetic, fi-cyclopentylpropionic, cyclohexylformic, cyclohexylace tic, B-cyclohexylpropionic, an aryl or alkarylacid, e.g., benzoic, 2,3-, or 4-methylbenzoic, 2,3-, 2,4-, 2,5., 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic 2 4,6-trimeth- 6 ylbenzoic, a-naphthoic, 3-methyl-oc-naphthoic, phenylace tic, phenylpropionic, etc.

17-carboxylic acid esters of 9(11)-dehydro-17-ethyltestosterone are prepared in the same manner from 9(11)- dehydro-17-ethyltestosterone.

EXAMPLE 5 9a-Br0m0-1lfl-Hydroxy-I7-Methylzestoster0ne (V) To a solution of one gram of 9(l1)-dehydro-l7-methyltestosterone (IV) in fifty milliliters of acetone was added dropwise, with stirring, at fifteen degrees centigrade, one gram of N-bromoacetamide dissolved in 25 milliliters of water. A solution of twenty milliliters of 0.8 N perchloric acid was then slowly added at the same temperature. After twenty minutes, there was added a sufficient amount of a saturated aqueous solution of sodium sulfite to discharge the yellow color of the solution. The resulting mixture was then diluted with milliliters of water thereby precipitating one gram of 9a-bromo-11B-hydr0xyl7-methyltestosterone as needles melting at 153 to 155 degres centigrade.

Similarly, l7-carboxylic acid esters of 9(11)-dehydrol7-methyltestosterone (V, R=CH R':-AC), e.g., an ester named in the paragraph following Example 4, preferably the acetate, are similarly converted to a 17-car boxylic acid ester of 9 x-bromo-1lfl-hydroxy-l7-methyltestosterone.

Reacting 9a-brorno-1lfi-hydroxy-l7-methyltestosterone or a l7-ester thereof named above, with sodium iodide in acetone, according to techniques known in the art, is productive of 9u-iodo-llfi-hydroxy-U-methyltestosterone and esters thereof, respectively.

9m-bromo-1lfi-hydroxy-l7-ethyltestosterone and 17-carboxylic acid esters thereof are similarly prepared by substituting 9(11)-dehydro-17-ethyltestosterone and 17-carboxylic acid esters thereof, respectively, as the starting steroid in the reaction described in Example 5.

In the reaction of Example 5, the N-bromoacetamide produces hypobromous acid in situ. Other N-bromoamides and N-bromoimides may be used or a solution of hypobromous acid per so may be used.

EXAMPLE 6 9,1 1 B-Epoxy-J 7 M ezhy [testosterone (VI) A suspension of one gram of 9oz-bIOm0-l1fi-hYdIOXY- Calculated for C H O C, 75.92; H, 8.92. Found:

In the same manner as described in Example 6, 17- esters of 9a-bromo-11[i hydroxy-l7-rnethyltestosterone, e.g., 9a-bromo-1lfi-hydroxy-17-methyltestosterone, 17- acylates wherein the acyl radical is that of an acid named in the paragraph following Example 4, are converted to 17-carboxylic acid esters of 9,11,8-epoxy-17-methyltestosterone.

9,1l5-epoxy-17-methyltestosterone and 17-carboxylic 'acid esters thereof are also prepared by substituting 90- iodo-l 1 B-hydroxy-17-methyltestosterone and 17-carboxylic acid esters thereof, respectively, as the starting steroid in the reaction described in Example 6.

9,1lfi-epoxy-17-ethyltestosterone and 17 carboxylic acid esters thereof are similarly prepared by substituting 9ocbromo-llfi-hydroxy-17-ethyltestosterone and 17-carboxylic acid esters thereof, respectively, as the starting steroid in the reactlon describedin Example 6.

To a solution of 0.5 gram of 9,11,8-epoxy-l7-methyltestosterone (VI) in ten milliliters of methylene chloride was added two milliliters of 48 percent aqueous hydrofluoric acid. The mixture was stirred at room temperature for five hours and then cautiously poured with stirring into a mixture of six grams of sodium bicarbonate in a mixture of ice and water. The precipitated steroid was extracted with methylene chloride, the extract washed with water and then dried. The solvent was distilled from the dried solution and the residue crystallized from methylene chloride to give 148 milligrams of 9ot-fluoro-11fihydroxy-l7-methyltestosterone melting at 265 degrees Centigrade with decomposition, having an [@1 of plus 110 degrees in chloroform and the analysis below.

Calculated for C H F: C, 71.40; H, 8.69; F, 5.65. Found: C, 71.71; H, 8.66; F, 5.75.

Similarly, 9OC-fillOTQ-1 lfl-hydroxy-l7ethyltestosterone is prepared by substituting 9,1Iii-epoxy-l7-ethyltestosterone as the starting steroid in Example 7.

EXAMPLE 8 9-Flu0r0-1 1 -H y d oxy-l 7-01 6 th y l testosterone 17-Acetate (VII) Following the procedure of Example 7 exactly, but substituting a molar equivalent of 9,11B-epoxy-17-methyltestosterone, l7-acetate as the starting steroid, there is thus-produced 9a-fluoro-llfi-hydroxy-17-methyltest0sterone, 17-acetate.

Following the procedure described in Example 8, but substituting as starting steroid another l7-carboxylic acid ester of 9,1l 8-epoxy-l7-methyltestosterone, e.g., a 9,1113- epoxy-l7-methyltestosterone, 17-acylate wherein the acyl radical is that of an acid named in the paragraph following Example 4, there is thus-produced other 1.7-esters of 9oz-fiuoro-llfi-hydroxy-l7-rnethyltestosterone,' e.g., 90cfiuoro 11B hydroxy-17-metl1yltestosterone, l7-acylates wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve ecarbon atoms, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, iso'outyric, Valerie, isovaleric, trimethylacetic, 2- methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovalcric, cyclopropylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic, fi-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, fl-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2-, 3-, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, a-naphthoic, S-rnethyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic, phenylpropionic, etc.

Similarly, 9a-fiuoro-l'lfi-hydroxy-l7-ethyltestosterone, l7-acylates are prepared by substituting a 9,1118-epoxy-17- ethylte stosterone, 17-acy1ate, e.g., wherein the acyl radical is that of an acid named in the paragraph following Example 8, as the starting steroid in the reaction of Example 8. I

' 7 EXAMPLE 9 Qua-Ch loro-Z 1 5-11 ydi'Oxy-J 7 -M etlzyltestosterone Following the procedure of Example 7 exactly, but substituting anhy lrous hydrogen chloride for the hydrogen fiuoride, there .is thus produced 9a-chloro-11fl-hydroxy-i7-methyltesteosterone. 7

Similarly, 17-carboxylic acid esters, e.g., 9C'ChlOI'O-1 1B hydroxy-l7-methyltestosterone, 17-acylates wherein the acyl radical is that of an acid named in the paragraph following Example 4, are produced by substituting a 9,113- epoxy-l7-rnethyletestosterone, 17-acylate, e.g., wherein the acyl radicalis that of an acid named in the paragraph following Example 4, as the starting steriod in the reaction describedin Example 9. r 1

Following the procedure of Example 9,"but substituting as starting steroid 9,ll,B-epoxy-l7-ethyltestosterone or a 9,1I/S-epoxy-l7-ethyltestosterone, 17-acylate wherein the acyl radical is, for example, that of an acid named in the paragraph following Example 4, there is thus-produced 9ct-chloro-1lfi-hydroxy-17-ethyltestosterone and Qa-ClllOiO- 17-ethyltestosterone, 17-acylates, respectively.

The 9u-chloroand 9a-fluoro-l1B-hydroxy-l7-alkyltestosterones, 17-acylates named above are also prepared by esterification of the corresponding free 17-hydroxy compounds in the manner described in Example 4.

EXAMPLE 10 9a-Flll0i'O-11 -Kezo-1 7 -M ethyl testosterone (VIII To a solution of 0.457 gram of 9e-fiuoro-116-hydroxyl7-methyltestosterone (VII) in twenty milliliters of glacial acetic acid was added a solution of 0.25 gram of chromium trioxide and one'milliliter of water in twenty milliliters of acetic acid. The mixture was maintained at room temperature for 4.5 hours and then mixed with five milliliters of methanol. The solvent was removed by distillation at reduced pressure and the almost dry residue mixed with twentymilliliters of water. The precipitate was filtered, washed with water and then dried to give 0.362 gram of 9a-fiuoro-1l-keto-17-methyltestosterone melting at 208 to 212 degrees centigrade and, after crystallization from dilute methanol and then from a mixture of acetone and hexane hydrocarbons, melting at 213 to 220 degrees centigrade, having an [m1 of plus 144 degrees in chloroform and the analysis below.

Calculated for C20H27O3FZ C, 71.83; H, 8.14; F, 5.68 Found: C, 72.13; H, 8.30; F, 5.83.

Following the procedure described in Example 10, but substituting as starting steroida 9a-fluoro-11fl-hydroxy- 17-methyltestosterone, 17-acylate named in the paragraph following Example 4,. there is thus-produced esters of 9a.- fluoro-ll-keto-17-methyltestosterone, e.g., 9oz-flLIOXO-l1- keto-l7-methyltestosterone, 17-acylates wherein the acyl radical is, for example, that of an acid named in the paragraph following Example 4.

Similarly, substituting t-ChiO1'O-11 fi-hydroxy-l7-methyltestosterone as the starting steroid in the reaction described in Example 10, there is thus-produced 9oc-Chl010- 1 l-keto- 1 7-methyltestosterone.

Substituting 9ot-fluoro- 1 1e-hydroxy-17-ethyltestosterone or 9a-iluoro-llfi-hydroxy-17-ethyltestosterone, l7-acylates wherein the acyl radical is, for example, that of an acid named in the paragraph following Example 8 as the starting steroid in Example 10, there is thus-produced 9w fluoro-l l-keto-l7-ethyltestosterone and 9a-fluoro-11-keto 17-ethyltestosterone, l7-acylates, respectively. The 90:- chloro-l1-keto-17-ethyltestosterone and l7-acylates thereof are similarly prepared from the corresponding 9achloro-l ifi-hydroxy compounds.

Eight milliliters (0.068 mole) of ethyl oxalate and 10.6 milliliters (0.023 mole) of a 2.2 Normal methanolic solution of sodium methoxide is added to a solution of 6.3 grams (0.021 mole) of 9(11)-dehydro-l7-methyltestosterone in milliliters of anhydrous tertiary butyl alcohol at about fifty degrees Centigrade. The mixture is maintained at room temperature for three hours, during testosterone.

mole) of a 1.5 Normal methanolic solution of sodium methoxide whereafter the mixture is heated for five minutes on a steam bath followed by the addition of the cooled solution to water. A precipitate of 2-bromo-9 (l1)- dehydro-17-methyltestosterone forms, which is thoroughly Washed with water and dried in a vacuum desiccator.

A mixture of 758 milligrams (0.2 millimole) of 2- bromo-9(1l)-dehydro-17-methyltestosterone and 1.2 milliliter of 'y-collidine is heated at the refluxing temperature of the mixture for thirty minutes and then cooled to room temperature. The cooled mixture is diluted with ether and the collidine hydrobromide which precipitates is filtered from the solution. The filtrate is washed with dilute sulfuric acid followed by water and then dried over anhydrous sodium sulfate. The dried solution is freed of solvent and the oily residue chromatographed over four grams of alumina. The column is developed with Skellysolve B hexane hydrocarbons containing increasing amounts of acetone. 3-keto-17u-methyl-l,4,9(l1)-androstatrien-17B-ol is thus isolated from the other reaction products.

Following the procedures of Examples 5 to 7 exactly, but substituting 3-keto-17u-n1ethyl-1,4,9(1 1 )-androstatrien-17B-ol as the starting steroid, there is thus-produced 1 dehydro-9m-fiuoro-1lfi-hydroxy-17-methyltestosterone which is converted to l7-hydrocar'oon carboxylic acid esters thereof according to the procedure of Example 8 and the paragraph following. l-dehydro-9a-chloro-llfihydroxy-17-methyltestosterone is similarly prepared according to the procedure of Example 9, employing 3-ketoparagraph following Example 8.

1l-keto-l7-methyltestosterone and its esters are prepared by substituting 1-dehydro-9a-tluoro-11B-hydroxy-17-methyltestosterone and its l7-esters, respectively, in the reaction described in Example 10.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. l-dehydro-9ct-tluoro-1Lketo-17-methyltestosterone.

2. A' member of the group consisting of l-dehydro-Qafiuoro-ll-keto-17-methyltestosterone and its i7-acyl esters wherein the l7-acyl radical is that of hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inelusive.

Nobile June 3, 1958 Magerlein et al. June 10, 1958 

1. 1-DEHYDRO-9A-FLUORO-11-KETO-17-METHYLTESTOSTERONE. 